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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 1051-1056

Favorable results of patients with pT1a, b, c, lymph node-negative early breast cancer in the long interval


1 Department of Medical Oncology, Kanuni Sultan Suleyman Education and Search Hospital, Ankara, Turkey
2 Department of Medical Oncology, Ataturk Education and Search Hospital, Ankara, Turkey
3 MKA Clinic Center, Tepe Prime, Ankara, Turkey

Date of Web Publication4-Oct-2019

Correspondence Address:
Nilufer Bulut
Department of Medical Oncology, Kanuni Sultan Suleyman Education and Search Hospital,34313, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1275_16

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 > Abstract 


Background: The clinical characteristics of patients who had lymph node-negative early breast cancer were assessed.
Patients and Methods: We assessed a total of 576 patients in the study, including 74 patients (12.8%) with T1a, 119 patients (20.7%) T1b, and 367 patients (63.7%) with T1c. Patients with T1 tumors were further classified into three groups according to hormone receptor (HR) and human epidermal growth factor-receptor 2 (HER2) status.
Results: In patients with T1a, the disease-free survival (DFS) rate was 98.4% at 2 years (P = 0.001). In subgroup analysis of early breast cancers, 10-year-DFS rates of the patients in HR+/HER2–, HR–/HER2+, and HR–/HER2– subgroups were not significantly different (P = 0.917).
Conclusion: The T1a group had a worse prognosis than T1b and T1c groups in second years (P = 0.001); however, there was not statistically important difference between HR+, HER2+ and triple negative subgroups (P = 0.917). Although there are differences in patients and tumor features, the prognosis of patients with T1a, b, c N0M0 breast cancer is excellent.

Keywords: Early breast cancer, T1a, b, c, treatment


How to cite this article:
Bulut N, Ulas A, Altundag K. Favorable results of patients with pT1a, b, c, lymph node-negative early breast cancer in the long interval. J Can Res Ther 2019;15:1051-6

How to cite this URL:
Bulut N, Ulas A, Altundag K. Favorable results of patients with pT1a, b, c, lymph node-negative early breast cancer in the long interval. J Can Res Ther [serial online] 2019 [cited 2019 Dec 14];15:1051-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/1051/230011




 > Introduction Top


Early breast cancer comprises almost 50% of all breast cancer incidents. In some cases, only 10% of all breast cancer incidents were categorized in the early breast cancer category.[1] The American Cancer Society reported an incidence rate of 7% (70/100.000) for tumors <2 cm.[2] Patients with lymph node-negative invasive breast carcinomas ≤1 cm in size have a low incidence of recurrence. These tumors are most detected during a mammographic examination of breast tissue.

Most node-negative breast cancer incidents with the primary ≤2 cm (T1a, b, c N0M0) do not recur within ≥20 years of follow-up when treated with a mastectomy, lumpectomy, or a lumpectomy followed by radiation therapy (RT).[1],[3]

It has been reported that the prognosis of node-negative breast cancer <2 cm in diameter is excellent. Complete surgical resection of the primary tumor constitutes the majority of the treatment, even without systemic adjuvant therapy.[4] Since the subgroups of patients diagnosed with small, node-negative, human epidermal growth factor receptor 2 (HER2+), and T1c (11–19 mm) breast cancer tumors have an increased risk of recurrence, these patients are likely to benefit from adjuvant therapy. This is especially, true for young patients under 35 years of age with a poor prognosis. The biological factors of a high-grade tumor, HER2/neu status and high Ki-67, tumor size, nodal involvement, and lymphovascular invasion were associated with a high recurrence or high mortality rate.[4],[5],[6] These factors constitute individual risk factors for nonpalpable tumors estrogen receptor (ER+), tumor size <2 cm do not require Mammaprint and Oncotype Dx determination. Even if the genetic risk factors are high, patients do not benefit from chemotherapy.[7]

In this study, the overall prognosis of lymph node-negative invasive ductal carcinoma (IDC) of breasts that were ≤2 cm in size was investigated retrospectively. Prognostic and predictive factors in subgroups of patients were evaluated, and the patients to be candidates for systemic adjuvant and hormonal therapies were determined.


 > Patients and Methods Top


Women who were diagnosed with breast cancer between 1983 and 2015 in our clinic were included in this analysis. Moreover, T1a (>0.1 but ≤0.5 cm), T1b (>0.5 but ≤1 cm), and T1c (>1 cm but <2 cm) tumors were included in the study. Patient demographics were obtained from charts. Tumors were marked according to the modified Bloom–Richardson scoring system and staged according to the tumor, node, and metastasis criteria. The data on ER, progesterone receptor (PR), and HER2/neu were procured through standard clinical testing, using immune-histochemistry (IHC) for ER and PR and the HerceptTest for HER2/neu. The IHC was scored on a qualitative scale from 0 to 3+, based on an interpretation of the staining intensity, with 0 and 1+ categorized as negative (incomplete membrane staining in 10% of the tumor cells), 2+ as borderline, and 3+ as positive (strong and complete membrane staining in >10% of cells). For ER and PR, receptor positivity was based on >5% of cells testing positive with IHC.

Tumors that scored 2+ were further analyzed for HER2 amplification by means of fluorescence in situ hybridization. T1a, b, c N0M0 are types of Stage 1 breast cancer that are categorized according to size; T1a is no >0.5 cm, T1b is between 0.6 and 1.0 cm, and T1c is >1 cm but <2 cm. Furthermore, subtypes were defined as luminal A (ER+ and/or PR+, HER2−), luminal B (ER+/HER2+), HER2− enriched (ER−/PR−), and triple-negative (ER−/PR−/HER2−).

Conventionally, pathologic staging was identified with total mastectomy and Level 1–2 axillary dissection. A sentinel lymph node biopsy was used to mark the stage of the axilla by using a blue dye method. Lymphoscintigraphy was performed with intraoperative gamma probe. All of the lumpectomy-treated patients received RT. A total of 38 (6.6%) women were treated with surgery alone; 216 (37.4%) women received chemotherapy; 322 (55.9%) received only hormonal therapy (tamoxifen and/or aromatase inhibitor); and 116 (20.1%) received chemotherapy followed by hormonal therapy.

Statistical analysis

The differences in clinical and biological characteristics between T-stage subgroups were evaluated by a Chi-square test. The recurrence-free survival (RFS) curves were constructed using the Kaplan–Meier method, and the log-rank test was used for a comparison of the survival curves between subgroups according to prognostic factors. Moreover, the 5-year cumulative survival rate and the correlation between the probability of death or recurrence and clinical and biologic features were compared. A significance level of 0.05 was used for covariate entry. All statistical analyses were performed using SPSS (IBM, Armonic, NY, USA) for Windows software, version 15.0. Cox proportional analysis was not fit to determine the risk of recurrence due to similar DFS rates of groups. Multivariate analysis was not used.


 > Results Top


A total of 576 patients were included in the study. The median age was 54 (range: 27–86 years) among patients with T1a, T1b, and T1c tumors. Seventy-four patients (12.8%) had T1a tumors, 119 patients (20.7%) had T1b, and 367 patients (63.7%) had T1c tumors.

Seventy-five patients (14.6%) had HER2+ tumors; 81.7% had a hormone receptor (HR+) disease; and 12.4% had a triple-negative disease. Patients with T1 were further classified into HR+/HER2−, HR+/HER2+, HR−/HER2−, and HR−/HER2+ subgroups [Table 1].
Table 1: Baseline characteristics of all patients according to T stage

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A total of 280 patients (48.8%) had a mastectomy, and breast-conserving surgery (BCS) was performed on 297 (297 of 572) women (51.9%). Among patients who received BCS, 297 patients (51.9%) were treated with adjuvant radiotherapy after surgical resection. A total of 171 patients (29.6%) received systemic adjuvant therapy. We treated these patients with a mixed chemotherapy treatment consisting of a cyclophosphamide, methotrexate, fluorouracil, and anthracycline-based regimen. There was no change in chemotherapy regimens over time, but after 2006, the trastuzumab treatment was included in this study.

Among patients with HR+ disease, 439 (76.0%) received adjuvant endocrine therapy. A total of 73 patients (14.1%) were HER2+ and 46 patients (8.0%) at clinical high risk received adjuvant trastuzumab.

Three of the 37 (0.5%) patients in the T1a group, 13 of the 37 (2.3%) patients in the T1b group, and 21 of the 37 (3.6%) patients in the T1c group who were receiving hormonal therapy were switched from tamoxifen to aromatase inhibitors after 2 or 3 years. We followed up on 38 patients (6.6%) without any treatment. The median follow-up duration was 4.2 years. In patients with T1a, b, and c, the disease free-survival (DFS) rate was 98.4%, 100% and 100% in the second year, respectively (P = 0.001). At year 10, DFS rates of T1a, T1b, and T1c patients were 95.7%, 100% and 100%, respectively (P = 0.001). There was a difference at year 20 in the DFS rates of T1b and T1c patients (100% for T1b, 80% for T1c [P = 0.001]) [Figure 1]. Median overall survival rates could not be procured. In the subgroup analysis of T1, 2 and 10-year DFS rates were 99.7%, 93.4% in HR+/HER2−, 100% in both HR−/HER2−, and 100% in both HR−/HER2+ patients, respectively. There was no significant difference between HR+/HER2−, HR−/HER2−, and HR−/HER2+ subgroups (P = 0.917) [Figure 2].
Figure 1: Recurrence-free survival according to T1 size

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Figure 2: Analysis of disease-free survival of four breast cancer subtypes by log-rank test

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 > Discussion Top


It is standard practice to use adjuvant systemic therapy for all patients with a lymph node-positive disease.[8] There are many node-negative women who would benefit from adjuvant systemic therapy. The prognosis after surgical treatment in the T1a subgroup which will not receive systemic therapy is determined by the histopathologic features of the tumor. Some factors, such as HR status, HER2/neu overexpression, grade, lenfovascular invasion, tumor size, p53, and mitotic index are prognostic and predictive.[3] These factors predict the risk of recurrence and are used for the selection of patients for adjuvant systemic therapy.[1],[9]

Retrospective studies showed that T1a, b breast cancers were observed in a small population. Patients with Grade 3 tumors had a lower 10-year DFS rate when compared to Grade 1 and Grade 2 patients.[4] Age, tumor size, lymphovascular invasion, and estrogen-receptor negativity were commonly found to be poor prognostic factors.[3] Moreover, HER2+ disease is a recurrence risk factor in node-negative tumors.[4] In our study, there was no difference in the DFS rates between Grade 1, Grade2, or Grade 3 tumors in patients with T1 breast cancer (P = 0.130). In addition, statistically, there was no difference in the DFS rates of patients between ≤35 years and ≥35 years of age and HR-patients (P = 0.216 and P = 0.917, respectively) [Table 2]. HR+/HER2−, HR−/HER2−, and HR−/HER2+ subgroups had a good prognosis within 4.2 years (P = 0.917).
Table 2: Tumor features below and above the age of 35

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The purpose of adjuvant chemotherapy is to eradicate distant micrometastatic diseases. For node-negative patients, tumor size is one of the most powerful prognostic factors and is routinely used in making adjuvant treatment decisions.

In general, patients with small tumor sizes warrant consideration of adjuvant therapy since they may have a relapse risk of 20%–0%.[3],[5] In this study, a high lymphovascular invasion (LVI) in T1c tumors (P = 0.002) was defined. The presence of LVI had an effect with respect to the risk of recurrence (P = 0.033). Nearly 36 (6.3%) of the 367 patients with T1c tumors developed systemic relapse [Table 3].
Table 3: Metastasis rates according to tumor features

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It has been demonstrated in this study that adjuvant hormonal therapy and hormonal therapy plus chemotherapy decreased the risk of recurrence of and death from breast cancer.

ER+ tumors in patients were treated with chemotherapy and tamoxifen and/or aromatase inhibitors (20.1%), regardless of the type of surgery [Table 4]. The rates of relapse and metastases were low [Table 3]. ER+ tumors have reduced recurrence risk in the late interval. Especially, CMF for ER+ and AC for ER− chemotherapies reduced risk recurrence in the long term.[5],[10] Therefore, this study cannot show if the pattern of recurrence reflects the natural history of specific subgroups or is a response to adjuvant therapy. Early recurrences were seen frequently in this group as most T1a patients did not receive chemotherapy. They did not reach a lifespan as long as T1b and T1c patients.
Table 4: Distribution of the treatment according to tumor size

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Some studies showed that HER2/neu amplification was associated with worsened DFS rates. HER2+/HR− subgroup tumors reached shorter DFS rates than other breast tumor subgroups, particularly HER2+/HR− groups.[11] However, anthracycline-based chemotherapy regimens improved the risk of recurrence.[11],[12] Similar to this study, Kwon et al., found a good short-term prognosis in lymph node-negative breast cancers.[4] In a recent assessment of 194 node-negative pT1a, b breast cancer, 58% of the patients treated with adjuvant chemotherapy showed an excellent 5-year outcome irrespective of chemotherapy.[13] Very few women with small node-negative tumors (T1a, b N0) were included in large adjuvant trastuzumab studies. Retrospective studies showed poor outcomes for patients with small HER2+ tumors when compared to HER2− disease, particularly in those that recommended adjuvant trastuzumab therapy.[11],[14]

In this study, 73 patients had HER2+ T1N0 tumors and 46 received adjuvant trastuzumab therapy. However, an increased mortality rate was not seen in women with HER2+ that were not treated with adjuvant trastuzumab during the 5 years after diagnosis at the end of follow-up. A significant improvement in the survival rates of women who were treated with adjuvant trastuzumab could not be made, but guidance for the future research was presented. As a result, the combination of hormonal therapy and trastuzumab may be particularly beneficial for HR+/HER2+ patients (there was no significant difference between HR+/HER2−, HR−/HER2−, and HR−/HER2+ subgroups (P = 0.917); this deduction was made because there was no DFS difference.

According to the results of this study, the DFS rate was 98.4%, 100%, and 100% in the second year, respectively (P = 0.001) for patients with T1a, b, and c. The 11-year cumulative survival rate was 93.4% in HR+/HER2− and 100% in HR−/HER2+ and HR−/HER2− in patients (P = 0.917). Nearly 48 (8.3%) of the patients with T1a tumor received hormonal therapy. Sixteen (2.8%) T1a tumor patients were untreated after surgery. Forty-six (8.0%) women were treated with modified radical mastectomy and 28 (4.9%) women had BCS. All the BCS-treated patients received RT. In a study conducted by Kennecke et al., a subgroup of women with early ER+ breast cancer were identified to be at increased risk of recurrence within 2–5 years of diagnosis despite treatment with tamoxifen, just as observed in this study.[15],[16] The previous studies demonstrated that a high grade was prognostic of poorer outcomes among women with ER+ early breast cancer.[9],[15] Low ER levels were predictive of poorer outcomes among tamoxifen-treated patients.[15] The second recurrence peak is higher for ER+ and lower for ER− tumors.[9] These results were obtained from the literature. In this study, receptor levels were not assessed. Prognostic factors such as tumor size, grade, and HER2 status are listed in [Table 2].

Ipsilateral breast cancer recurrence may also be caused by tumor cells lodged within the breast, in which instance adjuvant RT is administered. RT causes both a conventional short-term tumoricidal effect and the so-called “tumor bed effect,” in which the radiation-induced vascular damage of the surrounding tissue more indirectly impairs tumor growth.[17] The different recurrence peak timing is related to a differential effect of RT on ER+ and ER− negative tumor cells. One hypotheses are that ER tumor cells display higher radiosensitivity than ER+ tumor cells.[17] The risk of a recurrence was greater in women who had tumors of ≥1 cm in size regardless of ER status (except Grade 1 tumors).[9],[18] The different proteins involved in ER+ cells alter the autophagy associated with radiotherapy; this is one of the genetic factors that determine the sensitivity or resistance of radiation.[19]

Tumors that were lymph node positive, Grade 3, and had low ER levels demonstrated a ≥5% annual risk of recurrence within the first 5 years after diagnosis with a peak annual risk of 7.6% during the 2nd year after diagnosis. The annual recurrence risk for women with Grade 1 or Grade 2 tumors was relatively consistent, at approximately 2% per year beyond the 1st year after diagnosis. Women who had lymph node-negative tumors had a persistent recurrence risk of approximately 2% per year.[15]

In this study, the difference between DFS rates may have been caused by the gene signature of patients with T1a in the second year. In the genetic analysis, four chromosomal regions associated with poor prognosis included: 17q12, 17q21.33-q25.1, 8p11.2, and 8q24.3 in ER+ HER2− breast cancers. This situation is associated with relative resistance to hormonal therapy. These amplification regions were strong predictors of the early recurrence of ER+ breast cancers.[16] In all subtypes of early-stage breast cancers, overall survival found to be similar in long term.[20] While 5-year DFS rates were not different in most study, in study of Houvenaeghel et al., were shorter DFS young, high grade, LVI+, HR+, and HER2− with T1a tumors.[21]

In estrogen-dependent breast tumors, aromatase over-expression may cause cell proliferation. The estrogen, epidermal growth factor (EGF)/EGF receptor, and c-kit pathways may also control snail and slug expression patterns. In breast carcinomas, snail transcription factors have been linked to tumor progression and invasiveness. Epithelial–mesenchymal transition (EMT) plays a significant role in the development of metastases. One of the hallmarks of EMT is the loss of E-cadherin and a gain of N-cadherin expression, which are regulated by transcription factors, such as snail, slug, and twist. The level of snail (P = 0.014) and twist (P = 0.006) expressions were associated with a worsened patient relapse-free period, specifically in patients with ER+ tumors (P = 0.039).[22] These transcription factors were affected by different promoters. Its mechanism was not yet fully illuminated. A pAkt expression is associated with a poor grade and positive nodal status in early breast cancer. In addition, pAkt and pErk1/2 led to a chemoresistance of breast cancer.[23] In our series, chemotherapy preferences were often anthracycline-based (5 fluorouracil, epirubicin, cyclophosphamide; 5 fluorouracil, antracyline, cyclophosphamide; cyclophosphamide, methotrexate, 5-florouracil vs).

An excellent prognosis of lymph node-negative IDC of breasts of 2 cm or less was determined in our series. Among the 576 patients, in the survival analysis, only 7.3% of the patients relapsed and 0.6% died during follow-up. Median overall survival rates could not be assessed. Patients may have had a good prognosis as a result of combination chemotherapy regimens and a nonaggressive biologic phenotype. A study conducted by You et al. showed a good prognosis in all molecular subtypes.[20] Current studies include a short follow-up for early breast cancer in patients (approximately 5 years).[4],[15],[20] In our patients who received radiation treatment after breast-conserving therapy, only surgery and chemotherapy and/or hormonal therapy were similar in disease-free survival rates.


 > Conclusion Top


The T1a group had a worse prognosis than the T1b and T1c groups in the 2nd year, but there was no statistically significant difference between HR+/HER2−, HR−/HER2−, and HR−/HER2+ groups. Although there were differences in patients and tumor features, the prognosis of patients with T1a, b, c N0M0 breast cancer was excellent. All T1 breast cancers were observed to have excellent long-term outcomes regardless of initial treatment. Recurrences and deaths are known to happen, even if less frequently, in small, node-negative breast cancer patients, and the decision on adjuvant treatments remains controversial. Even if histopathologic features of early-stage tumors offer good prognostic criteria, the genetic markers of tumors determine the prognosis.

Acknowledgment

This study's data were procured from Medical Oncology Institution of Hacettepe University.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Joensuu H, Isola J, Lundin M, Salminen T, Holli K, Kataja V, et al. Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: A nationwide population-based study. Clin Cancer Res 2003;9:923-30.  Back to cited text no. 1
    
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Kwon JH, Kim YJ, Lee KW, Oh DY, Park SY, Kim JH, et al. Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less. BMC Cancer 2010;10:557.  Back to cited text no. 4
    
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Rouanet P, Roger P, Rousseau E, Thibault S, Romieu G, Mathieu A, et al. HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: Results from a french regional cohort. Cancer Med 2014;3:134-42.  Back to cited text no. 11
    
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Mirtavoos Mahyari H, Khosravi A, Mirtavoos Mahyari Z, Esfahani Monfared Z, Khosravi N. Overexpression of HER2/neu as a prognostic value in Iranian women with early stage breast cancer; A single institute study. Iran Red Crescent Med J 2014;16:e16005.  Back to cited text no. 12
    
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Ho AY, Gupta G, King TA, Perez CA, Patil SM, Rogers KH, et al. Favorable prognosis in patients with T1a/T1bN0 triple-negative breast cancers treated with multimodality therapy. Cancer 2012;118:4944-52.  Back to cited text no. 13
    
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Kennecke H, McArthur H, Olivotto IA, Speers C, Bajdik C, Chia SK, et al. Risk of early recurrence among postmenopausal women with estrogen receptor-positive early breast cancer treated with adjuvant tamoxifen. Cancer 2008;112:1437-44.  Back to cited text no. 15
    
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Demicheli R, Ardoino I, Boracchi P, Coradini D, Agresti R, Ferraris C, et al. Recurrence and mortality according to estrogen receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast. BMC Cancer 2010;10:656.  Back to cited text no. 17
    
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Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, et al. Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 2001;93:112-20.  Back to cited text no. 18
    
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Chen X, Ma N, Zhou Z, Wang Z, Hu Q, Luo J, et al. Estrogen receptor mediates the radiosensitivity of triple-negative breast cancer cells. Med Sci Monit 2017;23:2674-83.  Back to cited text no. 19
    
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van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, et al. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat 2012;133:49-59.  Back to cited text no. 22
    
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